Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121554086 G>A
Position: (GRCh37/hg19):Chr11:121424795 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GAC to AAC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 17

Findings

In a study that included 15,808 Alzheimer’s cases and 16,097 control subjects from multiple European and American cohorts, this allele was observed twice among the AD cases (Holstege et al., 2022).

Previously, two Alzheimer’s patients enrolled in the French National Reference Center for Young Alzheimer Patients (Centre National de Référence Malades Alzheimer Jeunes, CNR-MAJ) were identified as carriers of this variant. The first carrier began exhibiting symptoms at 48 years of age, her APOE genotype was E3/E4, and her family history of AD was not known (Nicolas et al., 2016). The second carrier was 60 years old at symptom onset, with an APOE genotype E3/E3 (Nicolas et al., 2018). CNR-MAJ contributed data to the 2022 study cited above.

No additional carriers were found among 640 cases and 1268 controls from a multi-center Dutch sample, 1256 cases and 1938 controls from the European Early Onset Dementia Consortium, 332 cases and 676 controls of European ancestry from the United Kingdom and North America, or when the French dataset was extended to include 852 early onset AD cases, 927 late-onset cases and 1273 controls from the Alzheimer Disease Exome Sequencing France (ADESFR) project (Campion et al., 2019).

The D806N variant was selected for genotyping in a North American cohort of 217 early onset AD cases and 169 controls. The variant was not found in this cohort. Nor was it found by whole- exome or genome sequencing of 866 familial late-onset AD cases and 324 controls in the same study (Fernández et al., 2016).

Functional Consequences

Aspartate-806 is a conserved residue within the YWTD-repeated β-propeller and may be critical for maintaining the rigidity of the propeller (Andersen et al., 2023). Based on domain mapping of disease mutations, Andersen and colleagues predicted that mutations of aspartate-806 are highly likely to increase the risk of Alzheimer’s disease—variants in homologous positions in LDLR, LRP5, and LRP4 are linked to familial hypercholesterolemia, osteoporosis-pseudoglioma syndrome, and Cenani-Lenz syndactyly syndrome, respectively (Andersen et al., 2023).

The D806N variant impaired maturation (glycosylation) and trafficking to the plasma membrane of SORL1 overexpressed in HEK293 cells (Rovelet-Lecrux et al., 2021).

The variant was predicted to be deleterious by three algorithms: SIFT, Mutation Taster, and PolyPhen-2 (Nicolas et al., 2016).

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References

Paper Citations

1. Holstege H, Hulsman M, Charbonnier C, Grenier-Boley B, Quenez O, Grozeva D, van Rooij JG, Sims R, Ahmad S, Amin N, Norsworthy PJ, Dols-Icardo O, Hummerich H, Kawalia A, Amouyel P, Beecham GW, Berr C, Bis JC, Boland A, Bossù P, Bouwman F, Bras J, Campion D, Cochran JN, Daniele A, Dartigues JF, Debette S, Deleuze JF, Denning N, DeStefano AL, Farrer LA, Fernández MV, Fox NC, Galimberti D, Genin E, Gille JJ, Le Guen Y, Guerreiro R, Haines JL, Holmes C, Ikram MA, Ikram MK, Jansen IE, Kraaij R, Lathrop M, Lemstra AW, Lleó A, Luckcuck L, Mannens MM, Marshall R, Martin ER, Masullo C, Mayeux R, Mecocci P, Meggy A, Mol MO, Morgan K, Myers RM, Nacmias B, Naj AC, Napolioni V, Pasquier F, Pastor P, Pericak-Vance MA, Raybould R, Redon R, Reinders MJ, Richard AC, Riedel-Heller SG, Rivadeneira F, Rousseau S, Ryan NS, Saad S, Sanchez-Juan P, Schellenberg GD, Scheltens P, Schott JM, Seripa D, Seshadri S, Sie D, Sistermans EA, Sorbi S, van Spaendonk R, Spalletta G, Tesi N, Tijms B, Uitterlinden AG, van der Lee SJ, Visser PJ, Wagner M, Wallon D, Wang LS, Zarea A, Clarimon J, van Swieten JC, Greicius MD, Yokoyama JS, Cruchaga C, Hardy J, Ramirez A, Mead S, van der Flier WM, van Duijn CM, Williams J, Nicolas G, Bellenguez C, Lambert JC. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease. Nat Genet. 2022 Dec;54(12):1786-1794. Epub 2022 Nov 21 PubMed.
2. Nicolas G, Charbonnier C, Wallon D, Quenez O, Bellenguez C, Grenier-Boley B, Rousseau S, Richard AC, Rovelet-Lecrux A, Le Guennec K, Bacq D, Garnier JG, Olaso R, Boland A, Meyer V, Deleuze JF, Amouyel P, Munter HM, Bourque G, Lathrop M, Frebourg T, Redon R, Letenneur L, Dartigues JF, Génin E, Lambert JC, Hannequin D, Campion D, CNR-MAJ collaborators. SORL1 rare variants: a major risk factor for familial early-onset Alzheimer's disease. Mol Psychiatry. 2016 Jun;21(6):831-6. Epub 2015 Aug 25 PubMed.
3. Nicolas G, Acuña-Hidalgo R, Keogh MJ, Quenez O, Steehouwer M, Lelieveld S, Rousseau S, Richard AC, Oud MS, Marguet F, Laquerrière A, Morris CM, Attems J, Smith C, Ansorge O, Al Sarraj S, Frebourg T, Campion D, Hannequin D, Wallon D, Gilissen C, Chinnery PF, Veltman JA, Hoischen A. Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer's disease. Alzheimers Dement. 2018 Dec;14(12):1632-1639. Epub 2018 Aug 13 PubMed.
4. Campion D, Charbonnier C, Nicolas G. SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data. Acta Neuropathol. 2019 Aug;138(2):173-186. Epub 2019 Mar 25 PubMed.
5. Fernández MV, Black K, Carrell D, Saef B, Budde J, Deming Y, Howells B, Del-Aguila JL, Ma S, Bi C, Norton J, Chasse R, Morris J, Goate A, Cruchaga C, NIA-LOAD family study group, NCRAD. SORL1 variants across Alzheimer's disease European American cohorts. Eur J Hum Genet. 2016 Dec;24(12):1828-1830. Epub 2016 Sep 21 PubMed.
6. Andersen OM, Monti G, Jensen AM, deWaal M, Hulsman M, Olsen JG, Holstege H. Relying on the relationship with known disease-causing variants in homologous proteins to predict pathogenicity of SORL1 variants in Alzheimer's disease. 2023 Feb 27 10.1101/2023.02.27.524103 (version 1) bioRxiv.
7. Rovelet-Lecrux A, Feuillette S, Miguel L, Schramm C, Pernet S, Quenez O, Ségalas-Milazzo I, Guilhaudis L, Rousseau S, Riou G, Frébourg T, Campion D, Nicolas G, Lecourtois M. Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease. Acta Neuropathol Commun. 2021 Dec 18;9(1):196. PubMed.

Further Reading

No Available Further Reading